PROJECT SUMMARY Alzheimer?s disease (and related dementias ADRDs) are the leading cause of dementia in those over the age of 65. Attempts to develop therapeutics to treat the condition have, to date, yielded disappointing results in clinical trials. Neuropathologies associated with the disease include increased levels of proteotoxic species of both beta-amyloid (A?) and tau. A? and tau have both independently been hypothesized to be the primary agent driving ADRD-related neurodegeneration, although it is not clear that these ?proteinopathies? are the cause of these disorders. Neurotoxic proteins are certainly associated with intracellular and extracellular protein aggregates in the form of tangles and plaques. These pathological features contain other insoluble, aggregated cellular proteins. We and others have shown that increased protein insolubility is a feature of normal aging. The proteins that enter the ?insolublome? are enriched for lifespan determining functions, but it is not clear how normal aging processes and the ADRD disease processes are related. ?Geroscience? is a concept that unites research on normal aging processes and research on chronic progressive diseases such as AD. Integral to the Geroscience approach is that aging is a likely cause of multiple human chronic diseases. It follows that interventions that target aging will provide novel therapeutic avenues for distinct diseases including ADRDs. We have previously identified scores of chemical compounds that extend the lifespan of the nematode C. elegans and have preliminary data that some of these compounds promote general protein homeostasis and suppress aspects of neurological disease. Here we propose to exploit this resource to better understand the relationship between normal aging and ADRDs but also to develop new potential therapies. We propose to initially test the efficacy of aging interventions in C. elegans models of A? and tau neurotoxicity and in human cell-based models of ADRDs. We will then screen for effects on age-related protein insolubility in these models. We will use the powerful genetics of the worm and biochemical techniques to determine pathways and mechanisms in a subset of lead compounds. Finally, we will utilize mouse models of ADRDs, to gauge the effectiveness of aging intervention in the top 1-2 lead compounds. By undertaking such a ?Geroscience approach?, we aim to develop new methods to targeting the very earliest proteostatic changes that lead to AD.